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[Key note comment on the determination of glomerular filtration rate].

Glomerular filtration rate (GRF) is the most fundamental renal function. Determination of GFR is the most important examination in clinical nephrology. Cin is accepted as the gold standard of GFR, but, continuous infusion and the determination method of inulin (method of anthrone) are very troublesome. Interference of glucose in the serum and urine of patients with diabetes mellitus on the determination of inulin should be avoided. Ccr is widely used in the clinical field. Recently, the dynamics of creatinine in the body have been clarified. Variation of pool, generation rate, extrarenal excretion and tubular excretion of creatinine are found to change daily in the patient. Additionally, classical Jaffé's reaction involves non creatinine chromogen particularly in the serum. Though Jaffé's reaction with kinetic analysis improves the reliability of this reaction, the result is still unsatisfactory. There are several methods of enzyme assay are now using an autoanalyser, but, if we use many enzymes and reagents, the reliability of this method could not exceed that of Jaffé's method. Recently, HPLC is recommended as the standard method. 24-hr urine collection is also troublesome in the measurement of Ccr. I have found a good correlation between the estimated Ccr using Cockcroft and Gault's formula and Cin. Such prediction using serum creatinine concentration and few parameters should be developed. Radiolabelled agents have been widely used for the determination of GFR. However, in Japan, the methods of clearance of non radiolabelled contrast agents should be developed. Furthermore, a physical determination of GFR is necessary. In this workshop, these issues will be discussed by each speaker.

Animals↗

Application of newer clearance techniques for the determination of glomerular filtration rate.

Glomerular filtration rate (GFR) is the standard measure of renal function and is critical for the management of renal diseases. Rigorous assessment of GFR requires the measurement of renal clearance of a filtration marker, such as inulin. This method, however, is not suitable for routine clinical practice. Labelled compounds as alternative filtration markers provide accurate and precise GFR measurement, but their use may be limited for safety reasons. Thus investigators have proposed clearance procedures using minute doses of non-radioactive contrast agents, including iothalamate and iohexol. Their renal clearance provides similar accuracy as inulin clearance in GFR estimation, but the need of urine collection again poses certain limitations to the procedure. Thus, plasma clearance of suitable exogenous markers, such X-ray contrast media, has been suggested for measuring renal function, in which the elimination rate of the tracer after a single intravenous injection is evaluated. Plasma clearance of these markers estimated by multiple blood samples provides precise information, but repeated sampling makes this method cumbersome. Abbreviated kinetic profiles have been proposed to predict GFR from the plasma disappearance curve. The simplified method that uses a one-compartment model corrected by the Bröchner-Mortensen formula gives an excellent correlation with inulin clearance and is currently employed for measuring GFR in multi-centre clinical trials.

Contrast Media↗

Measurement of glomerular filtration rate.

Glomerular filtration rate (GFR) is the standard measure of renal function and is critical for the diagnosis and management of renal diseases. Rigorous assessment of GFR requires the measurement of renal clearance of an exogenous marker that is freely filtered by the kidney, and that does not undergo metabolism, tubular secretion or absorption, such as inulin. While its clearance provides the most accurate method of measuring GFR, it is not suitable for routine clinical practice. Labeled compounds as alternative filtration markers, including 125I-iothalamate and 99mTc-diethylenetriaminepenta-acetic acid (DTPA), provide accurate and precise GFR measurements, but their use may be limited for safety reasons. To avoid exposing patients to radiation, investigators have proposed clearance procedures using minute doses of non-radioactive contrast agents, including iothalamate (ionic) and iohexol (non-ionic). This approach provides similar accuracy to inulin clearance. The most important limitation of all renal clearance methods is that urine is collected by spontaneous voiding, stimulated by water loading, and thus subject to errors due to incomplete emptying of the bladder. Thus, plasma clearance of a suitable exogenous marker (51Cr-EDTA, 125I-iothalamate, iohexol) has been suggested for measuring renal function, in which the elimination rate of the tracer after a single intravenous injection is evaluated. Plasma clearance of these markers estimated by multiple blood samples provides more precise information, but repeated sampling makes this method cumbersome. To overcome this drawback, abbreviated kinetic profiles have been proposed to predict GFR from the plasma disappearance curve (elimination phase). On analyzing the data with a simplified method that uses a one-compartment model (six blood samples only in the elimination phase), corrected with the Bröchner-Mortensen formula, an excellent correlation was found with inulin clearance. This method is currently employed for measuring GFR in multicenter clinical trials.

Animals↗

Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 hour urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes.

OBJECTIVE: To evaluate whether the protein:creatinine ratio in spot morning urine samples is a reliable indicator of 24 hour urinary protein excretion and predicts the rate of decline of glomerular filtration rate and progression to end stage renal failure in non-diabetic patients with chronic nephropathy. DESIGN: Cross sectional correlation between the ratio and urinary protein excretion rate. Univariate and multivariate analysis of baseline predictors, including the ratio and 24 hour urinary protein, of decline in glomerular filtration rate and end stage renal failure in the long term. SETTING: Research centre in Italy. SUBJECTS: 177 non-diabetic outpatients with chronic renal disease screened for participation in the ramipril efficacy in nephropathy study. MAIN OUTCOME MEASURES: Rate of decline in filtration rate evaluated by repeated measurements of unlabelled iohexol plasma clearance and rate of progression to renal failure. RESULTS: Protein:creatinine ratio was significantly correlated with absolute and log transformed 24 hour urinary protein values (P = 0.0001 and P < 0.0001, respectively.) Ratios also had high predictive value for rate of decline of the glomerular filtration rate (univariate P = 0.0003, multivariate P = 0.004) and end stage renal failure (P = 0.002 and P = 0.04). Baseline protein:creatinine ratios and rate of decline of the glomerular filtration rate were also significantly correlated (P < 0.0005). In the lowest third of the protein:creatinine ratio (< 1.7) there was 3% renal failure compared with 21.2% in the highest third (> 2.7) (P < 0.05). CONCLUSIONS: Protein:creatinine ratio in spot morning urine samples is a precise indicator of proteinuria and a reliable predictor of progression of disease in non-diabetic patients with chronic nephropathies and represents a simple and inexpensive procedure in establishing severity of renal disease and prognosis.

Circadian Rhythm↗

Influence of ureteral catheter size on urinary flow rate and glomerular filtration rate in the rat.

The influence of ureteral catheter diameter on renal function was studied in rats during different diuretic states. Urinary flow rate and glomerular filtration rate were measured on each rat using ureteral catheters of two different internal diameters. In non-diuretic rats, urinary flow rate and glomerular filtration rate did not change according to the catheter diameter. In diuretic rats, urinary flow rate was from 40 to 70% lower with the smaller catheter. Differences became more marked as urinary flow rate increased. Glomerular filtration rates were about 20% lower when measured with small catheters. These results clearly demonstrate that the use of small diameter ureteral catheters during diuretic states leads to a decrease in glomerular filtration rate and urinary flow rate. The results also emphasize the importance of using large diameter catheters during such experimental conditions.

Animals↗

Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate.

Glomerular epithelial protein 1 (GLEPP1) is a receptor tyrosine phosphatase present on the apical cell surface of the glomerular podocyte. The GLEPP1 gene (PTPRO:) was disrupted at an exon coding for the NH(2)-terminal region by gene targeting in embryonic stem cells. Heterozygote mating produced the expected genotypic ratio of 1:2:1, indicating that the Ptpro(-/-) genotype does not lead to embryonic or neonatal lethality. Kidney and glomerular structure was normal at the gross and light microscopic levels. Scanning and transmission electron microscopy showed that Ptpro(-/-) mice had an amoeboid rather than the typical octopoid structure seen in the wild-type mouse podocyte and that there were blunting and widening of the minor (foot) processes in association with altered distribution of the podocyte intermediate cytoskeletal protein vimentin. Reduced filtration surface area in association with these structural changes was confirmed by finding reduced glomerular nephrin content and reduced glomerular filtration rate in Ptpro(-/-) mice. There was no detectable increase in the urine albumin excretion of Ptpro(-/-) mice. After removal of one or more kidneys, Ptpro(-/-) mice had higher blood pressure than did their wild-type littermates. These data support the conclusion that the GLEPP1 (Ptpro) receptor plays a role in regulating the glomerular pressure/filtration rate relationship through an effect on podocyte structure and function.

Albumins↗

Effect of aldose reductase inhibitor (tolrestat) on urinary albumin excretion rate and glomerular filtration rate in IDDM subjects with nephropathy.

OBJECTIVE: To explore the possible link between diabetic nephropathy and the enhanced activity of the polyol pathway, known to occur in IDDM subjects. RESEARCH DESIGN AND METHODS: We studied the effects of the aldose reductase inhibitor tolrestat (200 mg/day) on urinary albumin excretion rate and glomerular filtration rate in 20 IDDM patients with diabetic nephropathy. RESULTS: Six months of placebo treatment produced no significant changes in glomerular filtration rate, urinary albumin excretion rate, and renal plasma flow. Consequently, filtration fraction remained unchanged. During tolrestat treatment, glomerular filtration rate decreased from the basal value of 156 +/- 14 ml.min-1.1.73 m2 to 142 +/- 13.7 ml.min-1.1.73 m2 (P < 0.001) at 2 mo; 128 +/- 12.4 ml.min-1.1.73 m2 (P < 0.001) at 4 mo; and 123.7 +/- 13.0 ml.min-1.1.73 m2 at 6 mo. A significant decrease of urinary albumin excretion rate was observed during the trial (basal values 219 +/- 32.5 vs. 196.9 +/- 28.5 micrograms/min at 2 mo [P < 0.05]; 171.6 +/- 25.5 micrograms/min at 4 mo [P < 0.001]; and 58.6 +/- 19.3 micrograms/min at 6 mo [P < 0.001]). No significant change in renal plasma flow was seen during tolrestat treatment. Filtration fraction significantly decreased in the tolrestat group from the basal value of 0.23 +/- 0.02 to 0.21 +/- 0.01 at 2 mo (P < 0.005); 0.18 +/- 0.02 at 4 mo (P < 0.001); and 0.17 +/- 0.02 at 6 mo (P < 0.001). CONCLUSIONS: The polyol pathway is implicated in hemodynamic changes associated with early diabetic nephropathy, and aldose reductase treatment can positively influence these parameters.

Adult↗

Of mice and men and elephants: metabolic rate sets glomerular filtration rate.

Allometric scaling deals with the functional consequences of changes in size or scale among geometrically dissimilar animals (ie, animals differing in proportions). For adult mammals ranging in size and proportion from mouse to elephant, the data describe an interdependent set of functions consisting of metabolism (measured as metabolic rate), glomerular filtration rate (GFR), effective renal plasma flow, excretion of nitrogenous waste products, cardiac output, and pulmonary function-related variables. Within this set of functions, evidence indicates that metabolic rate is the primary process. One important design feature is given by the ratio of GFR to metabolic rate. Because this ratio is independent of size, it can be generalized to all mammals in this series. The numeric value of this ratio gives the optimal GFR for each unit of metabolic rate. A simple hypothesis is proposed: metabolic rate, the primary process, sets GFR. This relationship is unidirectional. A decrease in GFR, for example, caused by nephron loss, should not lead to a change in metabolic rate. This hypothesis was tested in four natural experiments: human growth and development, thyroid dysfunction, chronic renal failure, and hibernation. The results are consistent with this hypothesis.

Age Factors↗

Chromium-51 ethylenediamine tetraacetic acid glomerular filtration rate: a better predictor than glomerular filtration rate calculated by the Cockcroft-Gault formula for renal involvement in systemic lupus erythematosus patients.

OBJECTIVE: To investigate whether the ethylenediamine tetraacetic acid (EDTA) glomerular filtration rate (GFR) is a better indicator of the degree of renal involvement than serum creatinine concentration or creatinine clearance calculated by the Cockroft-Gault formula. METHODS: We studied prospectively all systemic lupus erythematosus (SLE) patients with normal or borderline serum creatinine concentration (<110 micromol/l) and urinary sediment abnormalities and/or proteinuria in the last 2 yr. EDTA-GFR, serum creatinine concentration, calculated creatinine clearance (Cockroft-Gault formula) and 24-h urine protein were determined at the same time. Renal biopsies were performed in patients with low values of EDTA-GFR or significant proteinuria. RESULTS: Twenty-three patients were identified, of whom 22 were females. The average age of the patients was 31.6+/-8.2 yr. Biopsies were assigned to WHO classes as follows: class II, 1 patient; class III, 6 patients; class IV, 10 patients; class V, 6 patients. The average serum creatinine concentration, EDTA-GFR and calculated creatinine clearance were 79.8+/-mol/l, 74.5 ml/min and 97 ml/min respectively. EDTA-GFR showed abnormal values (<80 ml/min) in 15 of the 23 patients (65.2%) while calculated creatinine clearance was abnormal (<80 ml/min) in three of the 23 patients (13%) (P<0.001). Using the Pearson correlation test, we did not find any correlation between EDTA-GFR or creatinine clearance values and the sum of activity and chronicity indices. CONCLUSION: GFR performed by EDTA-GFR correctly predicted renal involvement in SLE patients, whereas GFR calculated by the Cockcroft-Gault formula may have underestimated renal function. Significant numbers of patients with WHO class III, IV or V lupus nephritis may be missed if biochemical creatinine clearance or serum creatinine concentration alone is used to assess renal disease.

Adolescent↗

Effect of experimental diabetes on glomerular filtration rate and glomerular prostanoid production in the rat.

Glomerular hyperfiltration is an early functional renal lesion seen both in experimental and human diabetes mellitus. This increase in the glomerular filtration rate has been thought to be mediated, in part, by changes in vasoregulatory hormones such as the prostanoids. The present study was designed to measure glomerular prostanoid production in rats with experimental diabetes to determine whether the biochemical changes in prostanoid production could be consistent with the hemodynamic alterations noted. Sprague-Dawley rats were studied either 7 or 28 days after intravenous streptozotocin administration (60 mg/kg). Measurements of the glomerular filtration rate were performed in two groups of diabetic animals 28 days after streptozotocin administration: one group with intact prostanoid production, the other having received a cyclooxygenase inhibitor for the 4-week period. Similar studies were performed in nondiabetic control rats. Measurements of glomerular prostanoid production were performed in control and diabetic animals 7 days after streptozotocin administration. The results of these studies indicate that experimental diabetes mellitus is associated with an increase in the glomerular filtration rate and that this increase can be blocked by the administration of a cyclooxygenase inhibitor. In addition, the determination of levels of various glomerular prostanoids indicated an increased production of prostacyclin and a decreased production of thromboxane during this period of hyperfiltration. Thus, these data support the premise that altered prostanoid biosynthesis may be one of the biochemical mediators of the hyperfiltration seen in early experimental diabetes mellitus.

Animals↗

Experience with the cumulative integral method for measurement of glomerular filtration rate.

The glomerular filtration rate (GFR) was estimated using (125)I-iothalamate by the cumulative integral method in 95 subjects - 16 normal subjects and 79 patients with suspected or proved renal disease. This method is accurate, simple to perform and theoretically sound. It minimizes errors due to transit time and bladder storage. The normal range of GFR was determined to be 71 +/- 10 (two standard deviations) ml/min/m(2). In 66 patients serum creatinine levels were compared with the GFR value expressed per square metre. For any given serum creatinine level there is a wide range of GFR values. A serum creatinine value in the normal range, i.e. between 0.7 and 1.3 mg/dl, cannot be used to predict the patient's GFR. The micro blood sampling technique makes this method particularly useful in infants.

Adult↗

Cystatin C: an improved estimator of glomerular filtration rate?

BACKGROUND: Glomerular filtration rate (GFR) is routinely assessed by measuring the concentrations of endogenous serum markers such as blood urea nitrogen and serum creatinine (SCr). Although widely used, these endogenous markers are not ideal and do not perform optimally in certain clinical settings. The purpose of this review is to critically review the potential utility of cystatin C (CysC), especially in patient populations in which CysC may have an advantage over routinely used endogenous markers of GFR. APPROACH: In a narrative approach, we extensively review publications, primarily from the last 5 years, that address the development of methods to measure CysC, reference intervals, and the diagnostic accuracy of CysC to assess GFR. Between June 2000 and September 2001 Medline was searched using "cystatin c" as a textword, and articles that examined >75 individuals (except for renal transplant studies) and/or used accepted "gold standards" for assessing GFR were selected for inclusion. A total of 17 studies are reviewed that provide reference interval data for several populations. A total of 24 studies make conclusions about the utility of CysC vs SCr and/or creatinine clearance, with 20 providing data on the sensitivity and specificity of CysC for detecting impaired GFR. These publications are organized into subgroups that deal with specific patient populations or clinical situations. CONTENT: This review focuses on two areas: (a) the evolution of immunoassays used to determine the concentration of CysC in serum, their analytic sensitivity, and reference intervals; and (b) the diagnostic performance of CysC against other renal markers in the general population and in specific subpopulations of patients. SUMMARY: Studies of reference intervals for CysC overwhelmingly demonstrated that CysC values in blood are independent of age and sex. Of the 24 studies that examined clinical utility, 15 concluded that CysC is superior to SCr, whereas 9 concluded that CysC is equivalent but provides no advantage. Summary ROC plot analysis of 20 studies that provide sensitivity and specificity data strongly suggests that CysC will be superior to SCr for detecting impaired GFR. Taken together, it is clear that CysC performs at least as well as SCr in the population at large and that it is likely to be superior to SCr in specific patient populations.

Biomarkers↗

Autoregulation of the glomerular filtration rate and the single-nephron glomerular filtration rate despite inhibition of tubuloglomerular feedback in rats chronically volume-expanded by deoxycorticosterone acetate.

Tubuloglomerular feedback (TGF) function and autoregulation (renal blood flow RBF; glomerular filtration rate, GFR; single-nephron glomerular filtration rate, SNGFR) were examined in rats chronically treated with deoxycorticosterone acetate (DOCA) and given isotonic saline to drink. DOCA treatment depressed arterial plasma renin activity, expanded plasma volume by 25% and increased arterial blood pressure. Autoregulation of RBF and GFR was maintained in the DOCA animals above 90 mm Hg and 110 mm Hg respectively, whereby both GFR and RBF were lower than in controls. Micropuncture experiments demonstrated the absence of TGF in the DOCA animals. There was no difference between SNGFR values measured in the distal and proximal tubules, nor was there a significant response of SNGFR when loops of Henle were perfused with Ringer's solution at 20 nl/min. Loop perfusion in control rats with tubular fluid collected in DOCA rats elicited a normal TGF response, showing that TGF inhibition in the DOCA animals is due to changes in the function of the juxtaglomerular apparatus. In contrast to control rats, proximal SNGFR was perfectly autoregulated. These results suggest that TGF is not primarily responsible for autoregulation and that the vasodilatation normally resulting from acute TGF interruption is therefore compensated by some other mechanism such that RBF and GFR are lower than in controls.

Animals↗

Urinary albumin excretion rate and glomerular filtration rate in single-kidney type 2 diabetic patients.

OBJECTIVE: To evaluate the urinary albumin excretion rate (UAER) and the glomerular filtration rate (GFR) of single-kidney type 2 diabetic patients (SKD) and of single-kidney non-diabetic patients (SKN). RESEARCH DESIGN AND METHODS: Patients who had only one kidney for at least 5 years, with no renal disease or hypertension at the time of the nephrectomy and with no calculus or systemic disease at the time of the evaluation, were included in this controlled cross-sectional study A total of 20 SKD (8 men, age 62 +/- 9 years; diabetes duration 8.5 +/- 7 years), 17 SKN (2 men, age 57 +/- 13 years), and 184 type 2 diabetic patients who were matched to the single-kidney diabetic group for age, sex, and BMI were studied. UAER was measured by immunoturbidimetry in timed 24-h sterile urine, and GFR was determined by the 51Cr-EDTA single-injection method. RESULTS: SKD patients presented a higher proportion (8 of 20, 40%) of microalbuminuria (UAER 20-200 microg/min) than SKN patients (3 of 17, 17.6%) and type 2 diabetic patients (37 of 184, 20%). SKD patients presented a higher proportion of macroalbuminuria (UAER >200 microg/min; 6 of 20, 30%) than SKN patients (1 of 17, 6%) but were similar to type 2 diabetic patients (43 of 184, 23%). The GFRs of normoalbuminuric SKN (71.7 +/- 21.4 ml x min(-1) x 1.73 m(-2)) and SKD patients (73.0 +/- 21.5 ml x min(-1) x 1.73 m(-2)) were similar but higher than the one-kidney GFR (GFR / 2) of the age-, sex-, and BMI-matched normal individuals (50.5 +/- 9.0 ml x min(-1) x 1.73 m(-2)) and normoalbuminuric type 2 diabetic patients (54.0 +/- 11.6 ml x min(-1) x 1.73 m(-2)). CONCLUSIONS: Increased GFR related to single-kidney status confers an increased risk of developing renal disease in the presence of diabetes.

Adult↗

Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients.

BACKGROUND: Predictors of diabetic nephropathy are only partly known. The role of glomerular hyperfiltration is much discussed. We have studied the cumulative incidence of micro and macroalbuminuria and the predictive value of glomerular filtration rate (GFR) and screening value of albumin excretion rate (AER) in type-1 diabetes. METHODS: A cohort of diabetic children was followed up at a mean duration of 29+/-3 years. All 75 children treated in one hospital with diabetes duration > or =8 years were prospectively followed for 8 years examining GFR, AER, blood pressure and HbA1c. After another 8-10 years, 60 of them were traced for endpoint follow-up. RESULTS: Seven patients (12%) developed macroalbuminuria, i.e. persistent overnight AER>200 mg/min, 12 (20%) developed persistent microalbuminuria (AER 15-200 mg/min) and 17 (28%) transient microalbuminuria (>15 mg/min on two consecutive occasions, normalized at endpoint). One baseline screening value of 24-h AER>15 mg/min predicted 93% of patients with persistent micro or macroalbuminuria. The negative predictive value was 78%. Six of seven macroalbuminuric and 10 of 12 microalbuminuric patients had a baseline GFR above the normal limit of the method (> or =125 ml/min/1.73 m(2)). When adjusted for diabetes duration, increased GFR predicted macro or microalbuminuria (odds ratios=5.44, P=0.04). The positive predictive value for having an increased baseline GFR was 53%. The negative predictive value was 77%. Stratification for HbA1c did not change the effect of an increased GFR. CONCLUSIONS: At a mean diabetes duration of 29 years the cumulative incidence of macroalbuminuria was 12%; however, another 20% had persistent microalbuminuria. A screening value of 24-h AER >15 mg/min was a strong predictor, whereas increased GFR was a weaker but significant predictor for micro and macroalbuminuria.

Albuminuria↗

The glomerular filtration rate during pregnancy: saline infusion enhances the glomerular filtration rate in the pregnant rat.

The glomerular filtration rate (GFR) of pregnant rats is generally believed to exceed non-pregnant values. This notion is primarily based upon standard insulin clearances. However, the insulin clearance requires continuous infusion of insulin usually dissolved in saline. Since saline infusion per se in pregnancy may influence the GFR, in the present study the effect of saline infusion upon the GFR in pregnant as compared with cyclic rats was investigated using various methods. The standard insulin clearance was compared using the standard 51Cr-EDTA method which does not require saline infusion. Clearance of insulin dissolved in glucose (5% in distilled water) instead of saline was also tested, while the 51Cr-EDTA method was employed using additional fluid infusion with either saline or 5% glucose in distilled water in an identical manner as compared with the insulin method. The GFR was also studied in conscious rats using 51Cr-EDTA clearance with and without fluid infusion. The distribution volume of 51Cr-EDTA was measured in nephrectomized rats (pregnant and cyclic) with and without saline or glucose infusions. The results show a significant increase of the GFR in pregnant rats as compared with cyclic rats only when saline was infused during the measurement; thus, GFR measurements without fluid infusion or replacement of saline by glucose during the measurements did not show a significant increase of GFR in pregnant rats. The volume of distribution per gram body weight of 51Cr-EDTA after saline infusion, but not after glucose infusion, was significantly increased as compared with the values obtained without additional infusion. It is concluded that the increase of the GFR seen in pregnant rats when either the 51Cr-EDTA method or the insulin method is accompanied by saline loading is rather due to infusion of saline in the pregnant animal and not a result of the pregnant condition per se.

Animals↗

The relation between tissue kallikrein excretion rate, aldosterone and glomerular filtration rate in human pregnancy.

The changes in renal kallikrein synthesis through normal pregnancy and its relation to aldosterone excretion and the glomerular filtration rate was investigated. Overnight urinary kallikrein and aldosterone excretion rates and glomerular filtration rate were measured at 18 weeks, 34 weeks, term and postpartum in normal human pregnancy. Kallikrein excretion was raised at 18 weeks compared with the nonpregnant state (P < 0 x 001) but was significantly reduced at term. The reduction in renal kallikrein was not due to falling aldosterone concentration, which increased in the third trimester, compared with 18 weeks (P = 0 x 002) and remained elevated at term compared with the nonpregnant state (P < 0 x 001). Glomerular filtration rate remained elevated at term despite the reduced kallikrein excretion rate. These data are consistent with the hypothesis that increased aldosterone production is one factor responsible for increased kallikrein synthesis which contributes to elevated glomerular filtration rate in early pregnancy. Other factors clearly inhibit renal kallikrein production at term. In the face of plasma volume expansion associated with increased mineralo-corticoid production, the effects of reduced kallikrein synthesis at term on glomerular perfusion and reabsorption of sodium by the distal tubule may predispose to blood pressure elevation in late pregnancy.

Aldosterone↗